Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution

Shen, Huaizong; Zhou, Qiang; Pan, Xiaojing; Li, Zhangqiang; Wu, Jianping; Yan, Nieng

doi:10.1126/science.aal4326

Cited by 371 publications

(476 citation statements)

References 102 publications

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“…43,44 While the exact mechanism of voltage-dependent activation of Na + channels is not fully determined, it is thought that the S4-S5 linker translates voltage-dependent shifts of the S4 segment into opening of the pore, 45 with motion of S4-S5 coupled to that of neighboring S5 and S6 segments. 46 …”

Section: Discussionmentioning

confidence: 99%

Mutations in SCN3A cause early infantile epileptic encephalopathy

Zaman

Helbig

Božović

et al. 2018

Annals of Neurology

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Section: Discussionmentioning

confidence: 99%

Mutations in SCN3A cause early infantile epileptic encephalopathy

Zaman

Helbig

Božović

et al. 2018

Annals of Neurology

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“…Recent studies with the cryo-electron microscopy method has greatly advances research on sodium channels by revealing the three-dimensional structure of a four-domain sodium channel for the first time [65]. The sodium channel from cockroach has the same fold of its core transmembrane segments as the bacterial sodium channels.…”

Section: Structure Of a Eukaryotic Sodium Channelmentioning

confidence: 99%

Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy

2017

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Voltage-gated sodium channels initiate action potentials in brain neurons. In the 1970’s, much was known about the function of sodium channels from measurements of ionic currents using the voltage clamp method, but there was no information about the sodium channel molecules themselves. As a postdoctoral fellow and staff scientist at the National Institutes of Health, I developed neurotoxins as molecular probes of sodium channels in cultured neuroblastoma cells. During those years, Bruce Ransom and I crossed paths as members of the laboratories of Marshall Nirenberg and Philip Nelson and shared insights about sodium channels in neuroblastoma cells from my work and electrical excitability and synaptic transmission in cultured spinal cord neurons from Bruce’s pioneering electrophysiological studies. When I established my laboratory at the University of Washington in 1977, my colleagues and I used those neurotoxins to identify the protein subunits of sodium channels, purify them, and reconstitute their ion conductance activity in pure form. Subsequent studies identified the molecular basis for the main functions of sodium channels—voltage-dependent activation, rapid and selective ion conductance, and fast inactivation. Bruce Ransom and I re-connected in the 1990’s, as ski buddies at the Winter Conference on Brain Research and as faculty colleagues at the University of Washington when Bruce became our founding Chair of Neurology and provided visionary leadership of that department. In the past decade my work on sodium channels has evolved into structural biology. Molecular modeling and X-ray crystallographic studies have given new views of sodium channel function at atomic resolution. Sodium channels are also the molecular targets for genetic diseases, including Dravet Syndrome, an intractable pediatric epilepsy disorder with major co-morbidities of cognitive deficit, autistic-like behaviors, and premature death that is caused by loss-of-function mutations in the brain sodium channel NaV1.1. Our work on a mouse genetic model of this disease has shown that its multi-faceted pathophysiology and co-morbidities derive from selective loss of electrical excitability and action potential firing in GABAergic inhibitory neurons, which disinhibits neural circuits throughout the brain and leads directly to the epilepsy, premature death and complex co-morbidities of this disease. It has been rewarding for me to use our developing knowledge of sodium channels to help understand the pathophysiology and to suggest potential therapeutic approaches for this devastating childhood disease.

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“…[1][2][3][4][5][6][7] and cryoelectron microscopy, e.g. 8,9 Voltagegated channels (4 £ 6TM) have four voltage-sensing domains and a pore domain. The later contains four outer helices (S5s), four P-loops and four pore-lining inner helices (S6s).…”

Section: Introductionmentioning

confidence: 99%

Conservation and variability of the pore-lining helices in P-loop channels

Tikhonov

Zhorov

2017

Channels

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The family of P-loop channels, which play key roles in the cell physiology, is characterized by four membrane re-entering extracellular P-loops that connect eight transmembrane helices of the poreforming domain. The X-ray and cryo-EM structures of the open-and closed-state channels show conserved state-dependent folding despite the sequences are very diverse. In sodium, calcium, TRPV and two-pore channels, the pore-lining helices contain conserved asparagines and may or may not include p-helix bulges. Comparison of the sequence-and 3D-alignemnts suggests that the asparagines appeared in evolution as insertions that are accommodated in two ways: by p-helix bulges, which preserve most of inter-segment contacts, or by twists of the C-terminal thirds and switch of inter-segment contacts. The two possibilities should be considered in homology modeling of ion channels and in structure-based interpretations of numerous experimental data on physiology, pathophysiology, pharmacology and toxicology of the channels.

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Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution

Cited by 371 publications

References 102 publications

Mutations in SCN3A cause early infantile epileptic encephalopathy

Mutations in SCN3A cause early infantile epileptic encephalopathy

Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy

Conservation and variability of the pore-lining helices in P-loop channels

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